TABLE 2.
Acquired Resistance Across the Spectrum of EGFR and ALK Inhibitors
| TKI | Target-Dependent Mechanisms | Target-Independent Mechanisms |
|---|---|---|
|
| ||
| EGFR TKIs | ||
|
| ||
| Wild-type selective EGFR TKIs | Acquisition of a secondary mutation, most commonly T790M | HER2 amplification |
|
|
||
| MET amplification | ||
|
|
||
| PIK3CA mutation | ||
|
|
||
| EMT | ||
|
|
||
| Small cell transformation | ||
|
| ||
| Mutant-selective EGFR TKIs | Acquisition of a tertiary mutation, such as C797S or L718Q | HER2 amplification |
|
|
||
| Loss of T790M allele | MET amplification | |
|
|
||
| EGFR amplification | KRAS mutation | |
|
|
||
| Small cell transformation | ||
|
| ||
| ALK TKIs | ||
|
| ||
| First-generation ALK TKIs (crizotinib) | Acquisition of secondary mutations (> 10 reported), most commonly L1196M and G1269A | EGFR activation |
|
|
||
| ALK fusion gene amplification | MAPK pathway activation | |
|
|
||
| c-KIT amplification and SCF overexpression | ||
|
|
||
| SRC activation | ||
|
|
||
| IGF-1R activation | ||
|
|
||
| Ligand-mediated HER2/3 activation | ||
|
|
||
| Protein kinase C activation | ||
|
|
||
| Small cell transformation (rare) | ||
|
| ||
| Second-generation ALK TKIs (ceritinib, alectinib, and brigatinib) | Acquisition of secondary mutations, most commonly ALK G1202R | MAPK reactivation |
|
|
||
| SRC activation | ||
|
|
||
| PIK3CA mutations | ||
|
|
||
| MET amplification | ||
|
|
||
| EMT | ||
Abbreviations: ALK, anaplastic lymphoma kinase; EMT, epithelial-mesenchymal transition; IGF-1R, insulin-like growth factor 1 receptor; MAPK, mitogen-activated protein kinase; SCF, stem cell factor; SRC, SRC proto-oncogene, non-receptor tyrosine kinase; TKIs, tyrosine kinase inhibitors.